managing her2- positive breast cancer in the metastatic setting: the evolution of targeted therapies...

Managing HER2- Positive

Breast Cancer in the Metastatic Setting: The Evolution of

Targeted Therapies

Howard A. Burris III, MD, FACPChief Medical Officer and Director of Drug Development

Sarah Cannon Research InstituteMemphis, TN

Lee Schwartzberg, MDMedical Director, West Clinic

Chief, Division of Hematology/Oncology Professor of Medicine

University of Tennessee Health Science CenterMemphis, TN

22Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet. 2011.

Breast Cancer Mortality

Breast cancer mortality has dropped by nearly one-third since 1990

3

HER2+ Breast Cancer Subtypes

3

Breakdown of the 21% HER2+

Bauer K., Cancer. 2010;10:228.

ER+/PR+/HER2+

ER+/PR-/HER2+

ER-/PR+/HER2+

ER-/PR-/HER2+

10.8%

7.1%

3.3%

0.5%

N=114,786 ~21% HER2+~79% HER2-

44Onitilo A. Clin Med Res Opin. 2009;7(2):4-13.

Survival for HER2+ Subtypes

• Clinical and pathologic features and survival of the four subtypes were compared

• In ER/PR+,HER2-, chemotherapy conferred significant overall survival advantages

• Subtype comparison revealed statistically significant differences in outcomes

55

Akt

SOS

RAS

RAF

MEK

VEGF

MAPK P

P

PP

Receptor-specificligands HER1, HER2,

HER3, or HER4HER2

HER1(EGFR)

HER2 HER4HER3

Tyrosine kinasedomains

Plasmamembrane

PI3K

Cell proliferationCell survivalCell mobility and invasiveness

Cytoplasm

Nucleus

Transcription

Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness

Ross JS, et al. The Oncologist. 2009;14:320-368.

6

Current Assays of HER2/neu

Immunohistochemistry

‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)

Fluorescence in situ hybridization (FISH)

HER2 gene no amplification FISH negative

HER2 gene amplification FISH positive

Murthy SS, et al. Indian J Pathol Microbiol. 2011;54(3):532-538.

7

Optimal Testing Algorithm Immunohistochemistry (IHC)

Breast Cancer Specimen (invasive component)

Equivocal for HER2 protein expression IHC 2+

Equivocal HER2 gene amplification (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials)

Positive for HER2 protein expression IHC 3+ (defined as uniform

intense membrane staining of >30% of invasive tumor cells)

Negative for HER2 protein expression

IHC 0 or 1+

Negative for HER2 gene amplification

Positive for HER2 gene amplification

HER2 testing by validated IHC assay for HER2 protein

expression

Test with validated assay for HER2 gene amplification

8

Breast Cancer Specimen

HER2 testing by validated FISH assay for HER2 gene

amplification

Equivocal for HER2 gene amplification (FISH ratio 1.8-2.2 or

HER2 gene copy 4.0-6.0)

Count additional cells for FISH or retest, or test with HER2 IHC

Equivocal HER2 gene amplification result (Patients with HER2/CEP17 ratio ≥2.0 were eligible for the adjuvant trastuzumab trials)

Positive for HER2 gene amplification (FISH ratio >2.2 or HER2 gene copy

>6.0)

Negative for HER2 gene amplification (FISH ratio <1.8 or HER2 gene copy

<4.0)

HER2 gene no amplification FISH negative

HER2 gene amplification FISH positive

Optimal Testing Algorithm FISH

99

HER2+ Metastatic Disease Case Review

Treatment of a 53-Year-Old Woman With HER2-Positive Metastatic Inflammatory Breast Cancer

• A 53-year-old woman presents with T4 N2 M0 ER–/PR–/HER2+ (by fluorescence in situ hybridization) right inflammatory breast cancer

• She is treated with preoperative doxorubicin/cyclophosphamide (AC) chemotherapy with minimal response in the breast and axilla and in the diffuse erythema in the skin of the left breast

• Her disease is not operable with expectation of clear margins

1010

Polling Question 1

Which Neoadjuvant Treatment Would You Recommend?

Please see the multiple answer options on the right and select an answer. Once you submit your

answer, your answer selection will be compared with your peers’ responses. The best answer(s)

will be discussed in the subsequent slides and commentary.

Discussion

Case Review – Progression I

Howard A. Burris III, MD, FACP

Lee Schwartzberg, MD

1212

Case Review – Progression I

The patient is subsequently treated with 3 cycles of preoperative weekly paclitaxel/trastuzumab with no response, followed by worsening erythema extending onto her chest wall below her breast and ipsilateral and contralateral supraclavicular fossa.

1313

Polling Question 2

Which Treatment Would You Recommend for Case Progression I ?

Please see the multiple answer options on the right and select an answer. Once you submit your answer, your answer selection will be compared with your peers’ responses. The best answer(s) will be discussed in the subsequent slides and commentary.

Discussion

Case Review – Progression II



1515

Case Review – Progression II

• The patient is treated with capecitabine/lapatinib for 6 cycles, with improvement in the erythema and a 30% reduction in tumor volume in breast and all nodal metastatic disease

• She undergoes a left modified radical mastectomy and has diffuse residual disease in her breast and axilla with diffuse skin and tumor lymphovascular invasion

• The margins of resection are clear• She receives radiation therapy and resumes

capecitabine/lapatinib postoperatively; however, she develops signs of coronary spasm that require discontinuation of capecitabine

1616

Polling Question 3

Which Treatment Do You Recommend for Case Progression II?


Discussion

Case Review – Progression III



1818

Case Review – Progression III

• The patient continues lapatinib/trastuzumab for 9 months and then develops progressive disease over the right chest wall as well as bilateral supraclavicular adenopathy

• Restaging reveals new pulmonary metastases• Her physician is interested in enrolling her

in a trial evaluating investigational HER2-targeted agents and refers her to the ongoing phase IB trial of trastuzumab emtansine (T-DM1)/paclitaxel/pertuzumab

1919

Polling Question 4

Which of the Following Statements Regarding Novel HER2-Targeted Agents Is Correct?


Discussion



21

P

P

P

P

Cell growth, proliferation, survival, metastasis, angiogenesis

Akt/PKB

mTOR

S6K1

PI3-K

Lapatinib

EGFR HER2

4E-BP1

elF-4E

Protein synthesis

Neratinib

Pertuzumab

Trastuzumab

T-DM1

P

P

P

P

PTEN

VEGFR

VEGFBevacizumab

Targeted Agents for HER2+ Breast Cancer

22Spector N., J Clin Oncol. 2009;27:5838.

Proposed Mechanisms of Action of Trastuzumab

23

HER2 Targeting With Trastuzumab Has Changed the Natural History of HER2-Positive Advanced Breast Cancer

Dawood S., et al. J Clin Oncol. 2009;28:92.

1991-2007

2424

Polling Question 5

With which of the following statements regarding HER2+ MBC do you agree?


25

StudiesSlamon et al,

20011

Vogel et al,20022

Burstein et al, 20033

Marty et al, 20054

Kaufman et al, 20095

Valero et al 20116

N 469 114 54 186 207 263

Treatment AC/EC + H or T+H vs chemo

H VH D+H vs D

Anas + H vsAnas

DCbH vsD+H

Response Rate

50% vs 32%* 35% (IHC 3+)34% (FISH+)

68% 61% vs 34%*

20.3% vs 6.8%*

72% vs 72%

Median TTP

7.4 vs 4.6 mo*

3.8 mo (H at 4 mg/kg)3.5 mo

(H at 2 mg/kg)

NR 11.7 vs 6.1 mo*

4.8 vs2.4 mo*

10.3 vs 11.1 mo

Median PFS

NR NR NR NR 4.8 vs2.4 mo*

NR

Median OS 25.1 vs 20.3 mo*

24.4 mo NR 31.2 vs 22.7 mo*

28.5 vs 23.9 mo

37.4 vs 37.1 mo

AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant

1. Slamon DJ, et al. N Engl J Med. 2001:344(11):783-792; 2. Vogel CL, et al. J Clin Oncol. 2002;20:719-726; 3. Burstein HJ, et al. J Clin Oncol. 2003;21(15):2889-2895; 4. Marty M, et al. J Clin Oncol. 2005;23(19):4265-4274; 5. Kaufman B, et al. J Clin Oncol. 2009;27(33):5529-5537; 6. Valero V, et al. J Clin Oncol. 2011;29:149-156.

Trastuzumab in First-Line Treatment

26National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines, 2012 available at www.nccn.org.

NCCN Guidelines

Preferred agents for trastuzumab-exposed HER2 + disease

• Lapatinib + capecitabine• Trastuzumab + other first-line agents• Trastuzumab + capecitabine• Lapatinib + trastuzumab

27Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.

PTEN Lapatinib

P13K

pAkt

Ras

Raf

pErk

Shc

Grb2

So8

Phospholipid cell membrane

Lapatinib: Targeting HER2 and EGFR

• Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2– Blocks signaling through

EGFR and HER2 homodimers and heterodimers

– May also prevent signaling between ErbB1/ErbB2 and other ErbB family members

28

Randomized Phase III Study EGF10015

• Progressive, HER2+ MBC or LABC

• Previously treated with anthracycline, taxane, and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

N=528

* Trastuzumab must have been administered for metastatic diseaseGeyer C, et al. N Engl J Med. 2006;355:2733-2743.

29

Progression-Free Survival

Time (weeks)0 10 20 30 40 50 60 70

Cu

mu

lati

ve P

rog

ress

ion

-Fre

e S

urv

ival

(%)

0

10

20

30

40

50

60

70

80

90

100

0.000045P-value (log-rank, 1-sided)

73 (45%)45 (28%)Progressed or died

0.48 (0.33, 0.70)Hazard ratio (95% CI)

17.936.9Median PFS, wk

161160No. of pts

Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

Lapatinib + Capecitabine Capecitabine

Capecitabine

Lapatinib + Capecitabine

30

Overall Survival: Capecitabine ± Lapatinib

0.800P-value (log-rank, 2-sided)

29 (18%)29 (18%)Deaths

0.93 (0.55, 1.59)Hazard ratio (95% CI)

NRNRMedian OS

161160No. of pts

Time (weeks)0 10 20 30 40 50 70 90

Cu

mu

lati

ve S

urv

ival

(%

)

0

10

20

30

40

50

60

70

80

90

100

60 80

Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

CapecitabineLapatinib +

Capecitabine

Capecitabine

Lapatinib + Capecitabine

31

OS With Lapatinib ± Trastuzumab in MBC

OS OutcomeL

(n=145)L + T (n=146)

Died, n (%) 113 (78) 105 (72)

Median, mo 9.5 14

HR (95% CI) 0.74 (0.57-0.97)

Log-rank P-value 0.026

6 Month OS

80%

70%

12 Month OS

56%

41%

Blackwell KL, et al. San Antonio Breast Cancer Symposium (SABCS) 2009. Abstract 61.

Ali

ve w

ith

ou

t P

rog

ress

ion

(C

um

ula

tive

%)

Patients at Risk, n148148

LL + T

121102

8865

6447

4328

2513

0

20

40

60

80

100

0 5 10 15 20 25 35Months From Randomization

1

30

LL + T

32

Stratification:• T≤5 cm vs. T>5 cm• ER or PgR + vs.

ER & PgR –• N 0-1 vs N≥2• Conservative surgery

or not

Invasive operableHER2+ BCT>2 cm (inflammatory BCexcluded)LVEF50%N=450

34 weeks

52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinibtrastuzumab

FEC

X

3

SURGERY

RANDOMIZE

lapatinib

trastuzumab

lapatinibtrastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks6 wks

Baselga J, et al. SABCS 2010.

Neo-ALTTO: Study Design

33

L, lapatinib; T, trastuzumab; L+T, lapatinib plus trastuzumab; pCR, pathologic complete response.* Excludes 15 patients with non-evaluable nodal status

Baselga J, et al. SABCS 2010.

Neo-ALLTO: Pathologic Response

(%)

Re

sp

on

se

L T L+T

N=154 N=149 N=152

10

20

30

40

50

60

70

0

P=0.34

P=0.0001

24.7%29.5%

51.3%

pCRPathologic Complete Response

L T L+T

N=150* N=145* N=145*

20.0%

27.6%

46.9%P=0.13

P=0.001

tpCRLocoregional (total) pCR

Investigational Anti-HER2 Agents

3535

Polling Question 6

Which of the following have demonstrated benefit in patients with HER2+ MBC who experienced disease progression on trastuzumab?


3636

Polling Question 7

Which of the following is true of trastuzumab-DM1?


37

Trastuzumab-DM1

38

T-DM1 binds to the HER2 protein on cancer cells

T-DM1 Selectively Delivers a Highly Toxic Payload to HER2-Positive Tumor Cells

• Trastuzumab-like activity by binding to HER2• Targeted intracellular delivery of a potent antimicrotubule

agent, DM1

Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

39

Trastuzumab-TDM1

• Trastuzumab-DM1 (T-DM1) is a novel anti-HER2 antibody drug conjugate in development for treatment of HER2-positive metastatic breast cancer (MBC).T-DM1 combines the HER2-targeting properties of trastuzumab2 with targeted delivery of a highly potent anti-microtubule derivative, DM1– T-DM1 binds to HER2 with an affinity similar to that of

trastuzumab.– It is hypothesized that after binding to HER2,

T-DM1 undergoes receptor-mediated internalization, 7 resulting in intracellular release of DM1.

40

1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)

HER2-positive, recurrent locally advanced BC or MBC (n=137)

T-DM13.6 mg/kg Q3W until PDT-DM13.6 mg/kg Q3W until PD

Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W

+ Docetaxel

75 or 100 mg/m2 Q3W

Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W

+ Docetaxel

75 or 100 mg/m2 Q3W

CrossoverT-DM1CrossoverT-DM1PDPD

Perez EA, et al. ESMO 2010. Abstract LBA3. Perez EA, et al. ESMO 2010. Abstract LBA3.

TDM1 Versus Trastuzumab + Docetaxel 1st line

• Randomized, phase II, international, open-label study• HER2-positive, measurable disease required• Stratification factors

– World region, prior adjuvant trastuzumab therapy, disease-free interval

• Primary endpoints: PFS by INV, safety• Key secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control

41Perez EA, et al. Proc ESMO 2010. Abstract LBA3.

† Most common AEs, any grade, T + D: alopecia: 66.2%, neutropenia: 57.4%, diarrhea: 45.6% — these were 1.5%, 7.5%, and 10.4% in pts receiving T-DM1.

Most common AEs, any grade, T-DM1: nausea: 47.8%, fatigue: 46.3%, pyrexia: 35.8% — these were 39.7%, 46.2%, and 20.6% in pts receiving T + D.

T-DM1(n=67)

T + D(n=70)

Efficacy Summary

Overall response rate (ORR) 47.8% 41.4%

Safety Summary

Grade ≥3 adverse event (AE)† 37.3% 75.0%

T-DM1 Versus Trastuzumab (T) + Docetaxel (D) in HER2-Positive MBC With No Prior Chemotherapy for MBC

42

T-DM1 Activity: Improved PFS

42Hurvitz S, et al. ECCO-ESMO 2011. Abstract 5001.

Treatment with T-DM1 reduced the probability of disease progression or death by 41% compared with Trastuzumab + Docetaxel

HR=0.59, P=0.035

Med

ian

Pro

gre

ssio

n-F

ree

Su

rviv

al

(mo

nth

s)

trastuzumab + docetaxel

T-DM1

HER2+ locally advanced or metastatic

0

10

15

5

14.2

9.2

P=0.035

43

Patients with HER2+ locally advanced or metastatic breast cancer following treatment with a taxane

and trastuzumab

(N=980)

T-DM1 q3w(n=490)

T-DM1 q3w(n=490)

Lapatinib + Capecitabine q3w(n=490)

Lapatinib + Capecitabine q3w(n=490)

PD or unacceptable toxicity

ClinicalTrials.gov. NCT00829166.

EMILIA (TDM4370g) Phase III Study: T-DM1 Versus Lapatinib/Capecitabine in HER2+ MBC

• Primary endpoint: PFS by IRF, OS, safety• Secondary endpoints: QoL (FACT B), DOR, PFS

by investigator assessment

44ClinicalTrials.gov. NCT01120184.

PD

Trastuzumab + Taxane(n=364)

Trastuzumab + Taxane(n=364)

T-DM1 + Pertuzumab(n=364)

T-DM1 + Pertuzumab(n=364)

T-DM1 + Placebo(n=364)

T-DM1 + Placebo(n=364)

Patients with HER2+, previously untreated MBC

(N=1092)

Patients with HER2+, previously untreated MBC

(N=1092)

Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC

• Primary endpoints: PFS as assessed by IRF, AEs– Superiority design with a noninferiority analysis– Interim futility analysis: option to drop experimental arm

• Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR

45

Trastuzumab Pertuzumab

Fisher, et al. J. Mol. Biol. 2010;402:217-229.

HER2-Targeted Therapy With Pertuzumab

• Monoclonal antibody and pan-HER inhibitor• Binds to a distinct epitope on the HER2

extracellular domain• Prevents dimerization

46

HER2Ligand-binding domain

(inactive)

Cell membrane

Tyrosine kinase domain

Pertuzumab

Trastuzumab

Pertuzumab Recognizes Different Epitopes

47

HER2 receptor

Trastuzumab

Pertuzumab

Subdomain IV of HER2

Dimerization domain

of HER2

Junttila, et al. Cancer Cell. 2009.

Pertuzumab Demonstrates Synergistic Activity With Trastuzumab

• Preferentially inhibits ligand-independent HER2 signaling

• Prevents shedding of HER2 ECD• Flags cells for destruction by the

immune system

• Inhibits formation of HER2 dimer pairs• Suppresses multiple HER signaling

pathways, leading to a more comprehensive blockade of HER2-driven signaling

• Flags cells for destruction by the immune system

48

++++

+++

++

++

Signaling activity

+ ++

+

Homodimers Heterodimers

HER1:HER1

HER2:HER2HER3:HER3

HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3HER2:HER4

HER3:HER4

Tzahar E., et al. Mol Cell Biol. 1996. Sergina NV, et al. Nature. 445:437-441.

HER2:HER3 Dimers May Provide an Escape Mechanism From Trastuzumab

49

RRTreatment A: 400 patients

Docetaxel* + Trastuzumab + Pertuzumab

Treatment A: 400 patients

Docetaxel* + Trastuzumab + Pertuzumab

Treatment B: 400 patients

Docetaxel* + Trastuzumab + Placebo

Treatment B: 400 patients

Docetaxel* + Trastuzumab + Placebo

First-Line HER2-positive

MBC

First-Line HER2-positive

MBC

N=808 HER2-positive Metastatic Breast Cancer

Primary Outcome: Progression-Free Survival

First-Line MBCCould have received prior adjuvant trastuzumab

1:1 randomizationstratification by (1. pretreated or de novo, 2. region)

* At least 6 cycles of docetaxelBaselga J, et al. N Engl J Med. 2012;366:109-119.

CLEOPATRA: Phase III Trial Evaluating Adding Pertuzumab

50

CLEOPATRA: Response Data

1.5 1.53.8 8.314.6

20.8

74.665.2

5.5 4.2

0

10

20

30

40

50

60

70

80

90

100

Trastuzumab + Docetaxel + Pertuzumab

(n=343)

Trastuzumab + Docetaxel + Placebo

(n=336)

CR

PR

SD

PD

Not evaluable

Pat

ien

ts (

%)

ORR: 80.2%

ORR: 69.3%

Baselga J, et al. N Engl J Med. 2012;366:109-119.

51

CLEOPATRA: Independently Assessed PFS

100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

Months

0 5 10 15 20 25 30 35 40

Ptz + T + D: median 18.5 monthsPbo + T + D: median 12.4 months

(HR: 0.62;95% CI: 0.51-0.75;

P<0.0001)

Stratified by previous treatment status and region

Pts at Risk, nPtz + T + DPbo + T + D

402406

00

345311

267209

13993

8342

3217

107

00


52

CLEOPATRA: OS Curve

52Baselga J, et al. N Engl J Med. 2012;366:109-119.

53

CLEOPATRA: Safety

Adverse Events (%)

Trastuzumab + Docetaxel + Pertuzumab

(n=407)

Trastuzumab + Docetaxel + Placebo (n=397)

All Grades Grade 3/4 All Grades Grade 3/4

Diarrhea 66.8 7.9 46.3 5.0

Alopecia 60.9 NR 60.5 NR

Neutropenia 52.8 48.9 49.6 45.8

Nausea 42.3 NR 41.6 NR

Fatigue 37.6 NR 36.8 NR

Rash 33.7 NR 24.2 NR

Decreased appetite 29.2 NR 26.4 NR

Mucosal inflammation 27.8 NR 19.9 NR

Asthenia 26.0 NR 30.2 NR

Peripheral edema 23.1 NR 30.0 NR

Constipation 15.0 NR 24.9 NR

Febrile neutropenia 13.8 13.8 7.6 7.6

Dry skin 10.6 NR 4.3 NR

Leukopenia NR 12.3 NR 14.6


54Baselga J, et al. SABCS 2011. Abstract S5-5.

CLEOPATRA: Conclusions

• Adding pertuzumab to first-line trastuzumab/docetaxel in HER2+ locally recurrent or MBC improves PFS vs trastuzumab/docetaxel alone

• Median PFS prolonged 6.1 months according to independent review– PFS improvement consistent across nearly all patient subgroups – ORR higher with addition of pertuzumab to

trastuzumab/docetaxel

• Pertuzumab associated with increased incidence of mild and manageable diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin

• Incidence of cardiac toxicities comparable between treatment arms– Symptomatic LVSD: Ptz + T + D (1.0%) vs Pbo + T + D (1.8%)

55

Neratinib

Inhibitors of EGFR-receptors

Gajria D Chandarlapaty S. Expert Rev Anticancer Ther. 2011;11(2):263-75 Review.

Neratinib

56

Neratinib Description

• Neratinib is an oral, multi-targeted, irreversible tyrosine kinase inhibitor

• In preclinical studies, has been shown to target the ErbB1 (EGFR), ErbB2 (HER2), and ErbB4 (HER4) kinases

• Mechanism: covalently binds to ErbB2 at ATP binding site and inhibits tyrosine kinase activity resulting in G0/G1 cell cycle arrest

57

Randomized Phase II: Neratinib Versus Lapatinib + Capecitabine in Locally Advanced or MBC

Progression-Free Survival n Median PFS 95% CI P-valueNeratinib 117 4.5 mo 3.1–5.7 mo

0.231L + C 116 6.8 mo 5.9–8.2 moL, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.

Overall Survival n Median OS 95% CI P-valueNeratinib 117 19.7 mo 18.2 mo–NE

0.280L + C 116 23.6 mo 18.0 mo–NEL, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable.

Most Common Adverse Events Most frequently observed severe adverse events in the trial were diarrhea and hand-foot syndrome; 28% of the patients in the neratinib arm and 10% of the patients in the L/C arm of the trial experienced rade 3/4 diarrhea.

Combination Treatments of

Novel Anti-HER2 Agents

58

59

Pertuzumab + trastuzumab

(n=66)


(n=66)

Cohorts 1 and 21

HER2-positive MBC Progressed on trastuzumab +

chemotherapy (Cohorts 1 and 2, n=66)


chemotherapy (Cohorts 1 and 2, n=66)


chemotherapy (n=29)


chemotherapy (n=29)

Pertuzumab(n=29)

Pertuzumab(n=29)


(n=15)


(n=15)Cohort 32

1. Baselga J, et al. J Clin Oncol.. 2010; 28;1138-1144. Baselga J, et al. SABCS 2009.

Phase II Trial of Trastuzumab + Pertuzumab in HER2-Positive MBC Patients Progressing During Trastuzumab-Based Therapy

Primary objectives• Safety and efficacy

Population• ≤3 prior lines cytotoxic therapy (including adjuvant treatment)

60

Pertuzumab/Trastuzumab Combination Therapy More Active Than Treatment With Either Agent Alone

60

Cohorts 1 and 2 (P+H) (n=66)

Cohort 3 (P)(n=27)

Cohort 3(P&H)

CR (%) 7.6 0.0 0.0

PR (%) 16.7 3.4 21.4

ORR (%) 24.2 3.4 21.4

SD (%) 25.8 6.9 21.4

CBR (CR+PR+SD> 6 months)

50.0 10.3 37.5

PD (%) 50.0 82.8 57.1

CR, complete response; PR, partial response; SD, stable disease

* n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); †n=11, as at data cut-off 4/15 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); ‡at data cut-off, 21 (31.8%) patients had not experienced PD

1. Gelmon, et al. ASCO 2008; 2. Baselga, et al. JCO. 2010; 3. Baselga, et al. SABCS 2009.

61

Phase IB/II Trial of T-DM1 + Pertuzumab in Patients With Locally Advanced and MBC Who Were Previously Treated With Trastuzumab

Phase IB: 3+3 dose escalation• Cohort I: T-DM1 3.0 mg/kg; pertuzumab

(840 mg loading dose, 420 mg maintenance dose)• Cohort II: T-DM1 3.6 mg/kg; pertuzumab

(840 mg loading dose, 420 mg maintenance dose)

Phase II• Expansion at dose level established in Phase Ib

Dose escalation phase(completed)

Expansion phase(completed)

Phase IB/II: HER2-positive MBC in all therapeutic lines

(n=67)

Phase IB/II: HER2-positive MBC in all therapeutic lines

(n=67)

T-DM1 + pertuzumab(n=9)

T-DM1 + pertuzumab(n=9)

T-DM1 + pertuzumab(n=58, including

22 first line)

T-DM1 + pertuzumab(n=58, including

22 first line)

Primary endpoints• Safety• ORR by RECIST 1.0

Secondary endpoints• PFS• DoR

Heavily pretreated population• Median of 6 prior therapeutic agents

in the metastatic setting

Miller K, et al. ASCO 2010.

62

T-DM1 + Pertuzumab Shows Promising Efficacy in Patients Pretreated With Trastuzumab + Lapatinib

ResultsTotal, n (%)

(n=28)

PR 10 (35.7)

SD 13 (46.4)

PD 4 (14.3)

Missing 1 (3.6)

• ORR was 35.7% (10/28 patients), per investigator assessment– All responses were confirmed PRs– 1/13 patients with SD had an unconfirmed response

Miller K, et al. ASCO 2010.Miller K, et al. ASCO 2010.

63

T-DM1 + Pertuzumab Has an Encouraging Safety and Tolerability Profile

Key AE (%) Grade 3 (%) Grade 4 (%) Total (all grades) (%)*

Any Events 36.4 4.5 100

Fatigue 13.6 0 52.3

Nausea 4.5 0 5 .0

Thrombocytopenia 6.8 4.5 27.3

Diarrhea 2.3 0 25.0

Vomiting 4.5 0 22.7

AST increase 6.8 0 20.5

Dyspnea† 2.3 0 20.5

AST, aspartate aminotransferase

* One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment; †Primarily attributed to pneumonia or the disease under study (lung metastases and pleural effusions).

Miller K, et al. ASCO 2010 Poster 1012.

AST, aspartate aminotransferase

* One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment; †Primarily attributed to pneumonia or the disease under study (lung metastases and pleural effusions).

Miller K, et al. ASCO 2010 Poster 1012.

64

THP (n=107)docetaxel + trastuzumab +pertuzumab

THP (n=107)docetaxel + trastuzumab +pertuzumab

HP (n=107)trastuzumab + pertuzumab

HP (n=107)trastuzumab + pertuzumab

TP (n=96)docetaxel + pertuzumab

TP (n=96)docetaxel + pertuzumab

docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17

FEC q3w x 3trastuzumab q3w cycles 5–17FEC q3w x 3trastuzumab q3w cycles 5–17



Study dosing: q3w x 4

TH (n=107)docetaxel + trastuzumab

TH (n=107)docetaxel + trastuzumab

Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve and

primary tumors >2 cm (N=417)

BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel

* Locally advanced=T2-3, N2-3, M0 or T4a-c, any N, M0; operable=T2-3, N0-1, M0; inflammatory=T4d, any N, M0Gianni L, et al. SABCS 2010.

NEOSPHERE: Study Design

S

U

R

G

E

R

Y

S

U

R

G

E

R

Y

65

H, trastuzumab; P, pertuzumab; T, docetaxelGianni L, et al. SABCS 2010.

P=0.014150

40

30

20

10

0TH THP HP TP

pC

R,

%

95%

CI

P=0.0198

P=0.003

29.0

45.8

16.8

24.0

NEOSPHERE: pCR Rates

66

Clinical trials of both agents are ongoing, including pertuzumab and T-DM1 in combination

Summary: Pertuzumab and T-DM1 Are Promising New Therapeutic Agents for HER2-Positive MBC

Pertuzumab• First HER2 dimerization inhibitor• Has demonstrated encouraging clinical efficacy and

tolerability in combination with trastuzumab• Offers a more comprehensive approach to blocking

HER2-driven signaling than trastuzumab alone

T-DM1• First HER2-directed ADC delivering cytotoxic drug

specifically to HER2-positive tumor cells while retaining the biological activity of trastuzumab

• Has demonstrated encouraging clinical efficacy and tolerability in heavily pretreated patients

67

Women with previously untreated HER2-positive locally recurrent/metastatic

breast cancer

(N=424)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2 +

Bevacizumab 15 mg/kg, all given q3w(n=216)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2 +

Bevacizumab 15 mg/kg, all given q3w(n=216)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2,

both given q3w(n=208)

Trastuzumab 6 mg/kg† +Docetaxel 100 mg/m2,

both given q3w(n=208)

Treatment until disease progression or unacceptable toxicity*

Stratified by previous (neo)adjuvant taxane,adjuvant trastuzumab, hormone receptor status,

measurable disease

* Planned minimum of 6 docetaxel cycles administered; †Trastuzumab 8 mg/kg loading dose given.Gianni L, et al. SABCS 2011. Abstract S4-8.

• Primary endpoint: PFS (investigator assessed)• Secondary endpoints: OS, ORR, duration of response, TTF, safety

AVEREL: Study Design

68

• ORR similar between T + Doc + Bev and T + Doc in investigator assessment (74.3% vs 69.9, respectively; P=0.3492)

• ORR significantly higher with addition of Bev in IRC assessment (76.5% vs 65.9, respectively; P=0.0265)

Outcome, MonthsT + Doc + Bev

(n=216)T + Doc (n=208) HR (95% CI) P Value

Median PFS (Investigator assessment)

16.5 13.7 0.82(0.65-1.02)

0.0775

Median PFS(IRC assessment)

16.8 13.9 0.72 (0.54-0.94)

0.0162

Median OS 38.5 38.3 1.01(0.74-1.38)

(unstratified)

0.9543

0.94(0.68-1.30)(stratified)

0.7078

Gianni L, et al. SABCS 2011. Abstract S4-8.

AVEREL: PFS, Interim OS Analysis, and Response

69

AVEREL: Conclusions

• Addition of bevacizumab to first-line treatment with trastuzumab and docetaxel in patients with HER2-positive advanced breast cancer may prolong PFS– Findings not significant according to

investigator-assessed PFS (primary endpoint; P=0.0775)

– Findings significant according to independent review of PFS (exploratory endpoint; P=0.0162)

• Bevacizumab-associated AEs led to higher incidence of discontinuation of any study drug

Gianni L, et al. SABCS 2011. Abstract S4-8.

Discussion

Thank You!



managing her2- positive breast cancer in the metastatic setting: the evolution of targeted therapies...

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